Established risk factors only provide partial explanation for familial risk of rheumatoid arthritis.

Action Points

Most of the familial aggregation of rheumatoid arthritis can't be explained by currently established genetic or environmental risk. factors.

Note that the study suggests that many familial risk factors remain to be identified, in particular for seronegative RA.

Most of the familial aggregation of rheumatoid arthritis (RA) can't be explained by currently established genetic or environmental risk factors, a Swedish study suggested.

Xia Jiang, BSc, of the Karolinska Institute in Stockholm, and colleagues linked data on patients from a large case-control study to data on disease history among relatives of those patients as recorded in nationwide Swedish registers, and found that established nongenetic risk factors -- including smoking, alcohol intake, parity, silica exposure, body mass index (BMI), fatty fish consumption, and education -- did not explain familial risk of either seropositive or seronegative RA to any significant degree.

Similarly, genetic risk factors including shared epitope (SE) and 76 single-nucleotide polymorphisms (SNPs) did not explain any of the familial aggregation of seronegative RA and less than half of the familial aggregation of seropositive RA, they wrote in Arthritis and Rheumatology.

"Our results indicate that a substantial proportion of the heritability (of RA) remains unexplained," the authors stated. "And they also imply that for the foreseeable future, family history of RA will remain an important clinical risk factor for RA that cannot be replaced by genotyping of known risk loci or collection of specific risk factors."

After adjusting for each environmental risk factor individually, "we observed no appreciable change in the familial risk (OR 3.00-3.08)," the authors said.

Adjusted for genetic risk factors, the estimates for familial risk decreased moderately to a SE-adjusted OR of 2.69 (95% CI 2.17-3.33), a SNP-adjusted OR of 2.55 (95% CI 2.03-3.20), and an SE and SNP-adjusted OR of 2.44 (95% CI 1.93-3.07).

Stratified by ACPA status, investigators found that familial aggregation of RA had a stronger influence on ACPA-positive RA (unadjusted OR 4.10) than on ACPA-negative RA (unadjusted OR 1.61).

The familial risk of ACPA-positive RA did not change significantly when environmental factors were included in the analysis, but it dropped substantially when genetic risk factors were included in the analysis at an SE- and SNP-adjusted OR of 3.35.

In contrast, adjustment for genetic and nongenetic factors did not significantly decrease the familial risk of ACPA-negative RA.

"Established risk factors only provided an explanation for familial risk of RA in minor part, suggesting that many familial risk factors remain to be identified, in particular for seronegative RA," investigators concluded. "Family history of RA therefore remains an important clinical risk factor for RA, the value of which has not yet been superseded by other information."

A study limitation was that the proportion of people in the control arm who donated blood was higher among those with a family history of RA than those without. However, the authors explained that they were able to correct for this selective participation through multiple imputation.

The study was supported by the Swedish Foundation for Strategic Research, the Swedish Research Council, and the Innovative Medicines Initiatives.

Jiang and co-authors disclosed no relevant relationships with industry.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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